Method of preparing ezetimibe and intermediate thereof

ABSTRACT

Disclosed is a method of preparing ezetimibe, including cross-metathesis using a Grubbs 2 nd  catalyst and deprotection using a Pearlman&#39;s catalyst, and an intermediate thereof. The method of preparing ezetimibe is useful as an efficient ezetimibe synthesis technique in pharmaceutical fields using ezetimibe as a raw material.

CROSS-REFERENCE TO RELATED APPLICATIONS

The present application claims priority under 35 U.S.C. § 119 to KoreanPatent Application No. 10-2018-0020490, filed on Feb. 21, 2018, in theKorean Intellectual Property Office, the entire contents of each ofwhich are hereby incorporated by reference.

TECHNICAL FIELD

The present invention relates to a novel method of preparing ezetimibeand an intermediate thereof, and more particularly to a method ofpreparing ezetimibe using a Grubbs 2^(nd) catalyst and a Pearlman'scatalyst and to an intermediate thereof.

BACKGROUND ART

Ezetimibe (Chemical Formula a), which is a drug used as an inhibitor ofcholesterol absorption in small intestine, is used as a main material ofEzetrol and Vytorin, which are commercially available drugs for thetreatment of hyperlipidemia. The ezetimibe synthesis process, developedby Schering-Plough, is problematic because Grignard reagents andorganolithium reagents, which are difficult to handle and have a risk ofexplosion, are used, and moreover, hydrogen gas at 2 atm and 4 atm isused upon reduction and deprotection reactions. Therefore, it isnecessary to develop a new reaction capable of progressing under mildconditions to replace the reaction requiring such harsh conditions.[Chemical Formula a]

DISCLOSURE Technical Problem

The present inventors have studied mild reaction conditions byalleviating harsh reaction conditions typically using Grignard andorganolithium reagents in the synthesis of ezetimibe and thus haveascertained that ezetimibe may be synthesized by performing anintermolecular reaction under mild conditions through cross-metathesisusing a Grubbs 2^(nd) catalyst and by conducting deprotection of abenzyl group under mild reaction conditions using hydrogen gas atatmospheric pressure in the presence of a Pearlman's catalyst.

Accordingly, the present invention is intended to provide a method ofpreparing ezetimibe including a cross-metathesis reaction using a Grubbs2^(nd) catalyst and a deprotection reaction using a Pearlman's catalyst.

Technical Solution

Therefore, the present invention provides a method of preparingezetimibe, which is a compound of Chemical Formula 11, comprising thefollowing steps (1) to (7).

The method of preparing ezetimibe according to the present inventionincludes: (1) obtaining a compound of Chemical Formula 3 below byreacting a compound of Chemical Formula 1 below with a compound ofChemical Formula 2 below in the presence of DIPEA(diisopropylethylamine) and DMAP (dimethylaminopyridine); (2) obtaininga compound of Chemical Formula 5 below by reacting the compound ofChemical Formula 3 with a compound of Chemical Formula 4 below in thepresence of TiCl₄ and DIPEA; (3) obtaining a compound of ChemicalFormula 6 below by reacting the compound of Chemical Formula 5 in thepresence of BSA (bis(trimethylsilyl)acetamide) and TBAF(tetrabutylammonium fluoride); (4) obtaining a compound of ChemicalFormula 8 below by reacting the compound of Chemical Formula 6 with acompound of Chemical Formula 7 below in the presence of a Grubbs 2^(nd)catalyst and CuI; (5) obtaining a compound of Chemical Formula 9 belowby reacting the compound of Chemical Formula 8 in the presence ofPd(OAc)₂, benzoquinone and HClO₄; (6) obtaining a compound of ChemicalFormula 10 below by reacting the compound of Chemical Formula 9 in thepresence of an (R)-CBS (Corey-Bakshi-Shibata) catalyst and a boranedimethyl sulfide complex; and (7) obtaining a compound of ChemicalFormula 11 below by reacting the compound of Chemical Formula 10 in thepresence of palladium hydroxide on carbon and cyclohexane.

wherein Bn is benzyl.

wherein Bn is benzyl.

wherein Bn is benzyl.

wherein Bn is benzyl.

wherein Bn is benzyl.

wherein Bn is benzyl.

In addition, the present invention provides intermediates of the abovepreparation method, particularly a compound of Chemical Formula 4 below,a compound of Chemical Formula 5 below, a compound of Chemical Formula 6below, a compound of Chemical Formula 8 below, a compound of ChemicalFormula 9 below, and a compound of Chemical Formula 10 below.

wherein Bn is benzyl.

wherein Bn is benzyl.

wherein Bn is benzyl.

wherein Bn is benzyl.

wherein Bn is benzyl.

wherein Bn is benzyl.

Advantageous Effects

According to the present invention, a method of preparing ezetimibeincludes a cross-metathesis reaction using a Grubbs 2^(nd) catalyst anda deprotection reaction using a Pearlman's catalyst, wherebyintermolecular cross-metathesis is carried out under mild conditions,and mild conditions using hydrogen gas at atmospheric pressure areapplied, thus synthesizing ezetimibe.

Also, the method of preparing ezetimibe according to the presentinvention is useful as an efficient ezetimibe synthesis technique inpharmaceutical fields using ezetimibe as a raw material.

DESCRIPTION OF DRAWINGS

FIG. 1 schematically shows the overall process of preparing ezetimibeaccording to the present invention;

FIG. 2 shows the ¹H NMR spectrum of Compound 3;

FIG. 3 shows the ¹³C{¹H} NMR spectrum of Compound 3;

FIG. 4 shows the ¹H NMR spectrum of Compound 5;

FIG. 5 shows the ¹³C{¹H} NMR spectrum of Compound 5;

FIG. 6 shows the ¹⁹F NMR spectrum of Compound 5;

FIG. 7 shows the ¹H NMR spectrum of Compound 6;

FIG. 8 shows the ¹³C{¹H} NMR spectrum of Compound 6;

FIG. 9 shows the ¹⁹F NMR spectrum of Compound 6;

FIG. 10 shows the ¹H NMR spectrum of Compound 8;

FIG. 11 shows the ¹³C{¹H} NMR spectrum of Compound 8;

FIG. 12 shows the ¹⁹F NMR spectrum of Compound 8;

FIG. 13 shows the ¹H NMR spectrum of Compound 9;

FIG. 14 shows the ¹³C{¹H} NMR spectrum of Compound 9;

FIG. 15 shows the 1⁹F NMR spectrum of Compound 9;

FIG. 16 shows the ¹H NMR spectrum of Compound 10;

FIG. 17 shows the ¹³C{¹H} NMR spectrum of Compound 10;

FIG. 18 shows the ¹⁹F NMR spectrum of Compound 10;

FIG. 19 shows the ¹H NMR spectrum of Compound 11;

FIG. 20 shows the ¹³C{¹H} NMR spectrum of Compound 11; and

FIG. 21 shows the ¹⁹F NMR spectrum of Compound 11.

BEST MODE

According to the present invention, a method of preparing ezetimibe maybe performed as shown in FIG. 1. Specifically, the method of preparingezetimibe according to the present invention includes performing anintermolecular reaction under mild conditions through cross-metathesisusing a Grubbs 2^(nd)catalyst [step (4)], and performing deprotection ofa benzyl group in the presence of a Pearlman's catalyst under mildconditions using hydrogen gas at atmospheric pressure [step (7)],whereby ezetimibe is synthesized.

<Step (1)>

Step (1) is obtaining a compound of Chemical Formula 3 by reacting acompound of Chemical Formula 1 with a compound of Chemical Formula 2 inthe presence of DIPEA (diisopropylethylamine) and DMAP(dimethylaminopyridine).

Specifically, pent-4-enoic acid (Compound 1) and oxalyl chloride areadded to a solvent (e.g. DCM), added with DMF, reacted at about 40° C.(i.e. within the range from 30 to 50° C.), and then cooled to roomtemperature, after which the solvent is removed. Thereafter, theresulting product is added with a solvent and is reacted with a solutionof (S)-4-phenyloxazolidin-2-one (Compound 2) and DMAP dissolved in theabove solvent, thus obtaining(S)-3-(pent-4-enoyl)-4-phenyloxazolidin-2-one (Compound 3).

In the above reaction, oxalyl chloride may be used in an amount of 0.5to 2 equivalents, preferably 1 to 1.5 equivalents, and more preferably1.2 equivalents, based on the amount of Compound 1.

Also, DIPEA may be used in an amount of 1 to 3 equivalents, preferably1.5 to 2.5 equivalents, and more preferably 2 equivalents, based on theamount of Compound 1.

Also, DMAP may be used in an amount of 1 to 10 mol %, preferably 3 to 7mol %, and more preferably 5 mol %, based on the amount of Compound 1.

<Step (2)>

Step (2) is obtaining a compound of Chemical Formula 5 by reacting thecompound of Chemical Formula 3 with a compound of Chemical Formula 4 inthe presence of TiCl₄ and DIPEA.

Specifically, Compound 3 is dissolved in a solvent (e.g. DCM), cooled toabout −20° C. (i.e. within the range from −30 to −10° C.), added withTiCl₄, reacted, added with DIPEA, and reacted. The resulting reactionproduct is added to a solution of(Z)-1-(4-(benzyloxy)phenyl)-N-(4-fluorophenyl)methaneimine (Compound 4)in DCM, and is then reacted at about −20° C. (i.e. within the range from−30 to −10° C.), thus obtaining (S)-3-((R)-2-((S)-(4-(benzyloxy)phenyl)((4-fluorophenyl)amino)methyl)pent-4-enoyl)-4-phenyloxazolidin-2-one(Compound 5).

In the above reaction, TiCl₄ may be used in an amount of 0.5 to 2equivalents, preferably 1 to 1.5 equivalents, and more preferably 1.1equivalents, based on the amount of Compound 3.

Also, DIPEA may be used in an amount of 1 to 3 equivalents, preferably1.5 to 2.5 equivalents, and more preferably 2 equivalents, based on theamount of Compound 3.

<Step (3)>

Step (3) is obtaining a compound of Chemical Formula 6 by reacting thecompound of Chemical Formula 5 in the presence of BSA(bis(trimethylsilyl)acetamide) and TBAF (tetrabutylammonium fluoride).

Specifically, Compound 5 is added to a solvent (e.g. toluene), addedwith BSA, reacted at room temperature, added with TBAF-3H₂O, andreacted, thus obtaining(3R,4S)-3-allyl-4-(4-(benzyloxy)phenyl)-1-(4-fluorophenyl)azetidin-2-one(Compound 6).

In the above reaction, BSA may be used in an amount of 1 to 3equivalents, preferably 1.5 to 2.5 equivalents, and more preferably 2equivalents, based on the amount of Compound 5.

Also, TBAF.may be used in an amount of 1 to 10 mol %, preferably 3 to 7mol %, and more preferably 5 mol %, based on the amount of Compound 5.

<Step (4)>

Step (4) is obtaining a compound of Chemical Formula 8 by reacting thecompound of Chemical Formula 6 with a compound of Chemical Formula 7 inthe presence of a Grubbs 2^(nd) catalyst and CuI.

Specifically, Compound 6, 1-fluoro-4-vinylbenzene (Compound 7), a Grubbs2^(nd) catalyst and CuI are added to a solvent (e.g. ether), reacted atabout 40° C. (i.e. within the range from 30 to 50° C.), cooled to roomtemperature, and filtered through silica gel, thus obtaining(3R,4S)-4-(4-(benzyloxy)phenyl)-1-(4-fluorophenyl)-3-((E)-3-(4-fluorophenyl)allyl)azetidin-2-one(Compound 8).

In the above reaction, the Grubbs 2^(nd) catalyst may be used in anamount of 1 to 10 mol %, preferably 3 to 7 mol %, and more preferably 5mol %, based on the amount of Compound 7.

Also, CuI may be used in an amount of 1 to 50 mol %, preferably 5 to 20mol %, and more preferably 10 mol %, based on the amount of Compound 7.

<Step (5)>

Step (5) is obtaining a compound of Chemical Formula 9 by reacting thecompound of Chemical Formula 8 in the presence of Pd(OAc)₂, benzoquinoneand HClO₄.

Specifically, Pd(OAc)₂, benzoquinone and HClO₄ are added to a solvent(e.g. acetonitrile), deoxygenated with stirring, added with Compound 8dissolved in a solvent, and reacted, thus obtaining(3R,4S)-4-(4-(benzyloxy)phenyl)-1-(4-fluorophenyl)-3-(3-(4-fluorophenyl)-3-oxopropyl)azetidin-2-one(Compound 9).

In the above reaction, benzoquinone may be used in an amount of 0.5 to 5equivalents, preferably 1 to 2 equivalents, and more preferably 1.5equivalents, based on the amount of Compound 8.

Also, Pd(OAc)₂ may be used in an amount of 1 to 10 mol %, preferably 1to 5 mol %, and more preferably 3 mol %, based on the amount of Compound8.

<Step (6)>

Step (6) is obtaining a compound of Chemical Formula 10 by reacting thecompound of Chemical Formula 9 in the presence of a (R)-CBS catalyst anda borane dimethyl sulfide complex.

Specifically, the (R)-CBS (Corey-Bakshi-Shibata) catalyst and Compound 9are dissolved in a solvent (e.g. THF), stirred at about −20° C. (i.e.within the range from −30 to −10° C.), added with the borane dimethylsulfide complex, and reacted at about −20° C. (i.e. within the rangefrom −30 to −10° C.), thus obtaining(3R,4S)-4-(4-(benzyloxy)phenyl)-1-(4-fluorophenyl)-3-((S)-3-(4-fluorophenyl)-3-hydroxypropyl)azetidin-2-one(Compound 10).

In the above reaction, the (R)-CBS catalyst may be used in an amount of1 to 50 mol %, preferably 10 to 30 mol %, and more preferably 20 mol %,based on the amount of Compound 9.

Also, the borane dimethyl sulfide complex may be used in an amount of0.5 to 5 equivalents, preferably 1 to 2 equivalents, and more preferably1.2 equivalents, based on the amount of Compound 9.

<Step (7)>

Step (7) is obtaining a compound of Chemical Formula 11 by reacting thecompound of Chemical Formula 10 in the presence of palladium hydroxideon carbon (a Pearlman's catalyst) and cyclohexane.

Here, Compound 10, Pd(OH)₂/C (palladium hydroxide on carbon) andcyclohexane are added to a solvent (e.g. MeOH) under hydrogen gas (H₂)at about 1 atm (i.e. within the range from 0.5 to 1.5 atm), and reactedat about 70° C. (i.e. within the range from 60 to 80° C.), thusobtaining(3R,4S)-1-(4-fluorophenyl)-3-((S)-3-(4-fluorophenyl)-3-hydroxypropyl)-4-(4-hydroxyphenyl)azetidin-2-one(Compound 11).

In the above reaction, Pd(OH)₂/C may be used in an amount of 1 to 30 mol%, preferably 10 to 20 mol %, and more preferably 15 mol %, based on theamount of Compound 10.

Also, cyclohexane may be used in an amount of 0.5 to 5 equivalents,preferably 1 to 2 equivalents, and more preferably 1.1 equivalents,based on the amount of Compound 10.

A better understanding of the present invention will be given throughthe following example, which is merely set forth to illustrate thepresent invention but is not to be construed as limiting the scope ofthe present invention.

Example Step (1): Synthesis of(S)-3-(pent-4-enoyl)-4-phenyloxazolidin-2-one (Compound 3)

Pent-4-enoic acid (1, 2.04 mL, 20 mmol) was dissolved in a DCM(dichloromethane) solvent (66 mL) and oxalyl chloride (2.03 mL, 24 mmol)was then added dropwise thereto. Subsequently, DMF (dimethylformamide)(200 μL) was added thereto, and the reaction was carried out at 40° C.for 1 hr. The reaction solution was cooled to room temperature and thesolvent was removed therefrom using an evaporator. Subsequently, theresulting product was diluted with DCM (66 mL) and was then addeddropwise to a solution of (S)-4-phenyloxazolidin-2-one (2, 3590 mg, 22mmol), DIPEA (diisopropylethylamine) (6968 μL, 40 mmol), and DMAP(dimethylaminopyridine) (122.17 mg, 1 mmol) dissolved in DCM (36.6 mL).The resulting reaction solution was stirred at room temperature for 2hr. After completion of the reaction, the reaction was terminated with0.5 M HCl (50 mL), followed by extraction with DCM (60 mL, 20 mL×3). TheDCM layer was dried with anhydrous MgSO₄ and then filtered. Further,column chromatography (ethyl acetate:hexane=1:2) was performed, thusyielding a desired compound(S)-3-(pent-4-enoyl)-4-phenyloxazolidin-2-one (3, 4219 mg, 86%) (FIGS. 2and 3).

(S)-3-(pent-4-enoyl)-4-phenyloxazolidin-2-one (3)

4219 mg, 86%, White solid; Rf=0.5 (ethyl acetate:hexane=1:2); ¹H NMR(400 MHz, CDCl₃) δ 7.41-7.29 (m, 5H), 5.85-5.75 (m, ¹H), 5.43 (dd, J=8.7Hz, 3.6 Hz, ¹H), 5.06-4.95 (m, 2H), 4.69 (t, J=8.8 Hz, ¹H), 4.29 (dd,J=8.9 Hz, 3.64 Hz, ¹H), 3.07-3.03 (m, 2H), 2.39-2.34 (m, 2H); ¹³C{¹H}NMR (100 MHz, CDCl₃) δ 172.2, 153.9, 139.2, 136.7, 129.3, 128.9, 126.1,115.8, 70.2, 57.7, 35.0, 28.2; IR (KBr) 3069, 2979, 1780, 1706, 1385,1326, 1200, 1060 cm⁻¹; HRMS (EI) m/z: [M]⁺ Calcd for C₁₄H₁₅NO₃ 245.1052;Found 245.1051.

Step (2): Synthesis of (S)-3-((R)-2-((S)-(4-(benzyloxy)phenyl)((4-fluorophenyl)amino)methyl)pent-4-enoyl)-4-phenyloxazolidin-2-one(Compound 5)

(S)-3-(pent-4-enoyl)-4-phenyloxazolidin-2-one (3, 4219 mg, 17.2 mmol)was dissolved in a DCM solvent (86 mL) and then cooled to −20° C.Subsequently, TiCl₄ (1 M solution in DCM) (21.9 mL, 20.6 mmol) wasslowly added thereto. The resulting reaction solution was allowed toreact for 15 min. After 15 min, DIPEA (5992 μL, 34.4 mmol) was slowlyadded thereto. The reaction was carried out for 30 min, after which asolution of (Z)-1-(4-(benzyloxy)phenyl)-N-(4-fluorophenyl)methaneimine(4, 7878 mg, 25.8 mmol) dissolved in DCM (168 mL) was slowly addedthereto. The reaction was carried out at −20° C. for 2 hr. Subsequently,AcOH (acetic acid) (5.7 mL, 0.33 mL/mmol) was diluted with DCM (17.2 mL,1 mL/mmol) and then added to the reaction solution, followed by reactionfor 30 min. The temperature was elevated to room temperature, a 1 MH₂SO₄ aqueous solution (224 mL, 13 mL/mmol) was added thereto, and thereaction was further carried out for 30 min. The reaction was worked-upusing a NaHCO₃ aqueous solution (600 mL) and ethyl acetate (400 mL, 133mL×3). The ethyl acetate layer was dried with anhydrous MgSO₄ and thenfiltered. Further, recrystallization was performed using a MeOH/DCM(9/1) solvent. The obtained solid was filtered using MeOH, thus yieldinga desired compound (S)-3-((R)-2-((S)-(4-(benzyloxy)phenyl)((4-fluorophenyl)amino)methyl)pent-4-enoyl)-4-phenyloxazolidin-2-one (5,4735 mg, 50%) (FIGS. 4 to 6).

(S)-3-((R)-2-((S)-(4-(benzyloxy)phenyl)((4-fluorophenyl)amino)methyl)pent-4-enoyl)-4-phenyloxazolidin-2-one (5)

4735 mg, 50%, White solid; ¹H NMR (400 MHz, CDCl₃) δ 7.44-7.33 (m, 5H),7.18-7.14 (m, 3H), 7.08-7.05 (m, 4H), 6.89-6.86 (m, 2H), 6.77-6.72 (m,2H), 6.41-6.38 (m, 2H), 5.76-5.66 (m, ¹H), 5.41 (dd, J=8.5 Hz, 3.1 Hz,¹H), 5.03-4.98 (m, 5H), 4.67-4.56 (m, 2H), 4.41-4.37 (m, ¹H), 4.18 (dd,J=8.7 Hz, 3.1 Hz, ¹H), 2.49-2.41 (m, ¹H), 2.12-2.06 (m, ¹H); ¹³C{¹H} NMR(100 MHz, CDCl₃) δ 174.7, 158.3, 156.0 (J=234.9 Hz), 154.5, 143.0 (J=2.1Hz), 138.5, 137.1, 134.9, 133.1, 129.1, 128.7, 128.4, 128.2, 128.2,127.7, 125.4, 117.7, 115.6 (J=22.3 Hz), 115.13, 115.07, 115.0, 70.2,60.9, 58.1, 48.5, 34.9; ¹⁹F NMR (376 MHz, CDCl₃) δ −127.70; IR (KBr)3064, 2918, 1772, 1704, 1509, 1385, 1200 cm⁻¹; HRMS (EI) m/z: [M]⁺ Calcdfor C₃₄H₃₁FN₂O₄ 550.2268; Found 550.2266.

Step (3): Synthesis of(3R,4S)-3-allyl-4-(4-(benzyloxy)phenyl)-1-(4-fluorophenyl)azetidin-2-one (Compound 6)

(S)-3-((R)-2-((S)-(4-(benzyloxy)phenyl)((4-fluorophenyl)amino)methyl)pent-4-enoyl)-4-phenyloxazolidin-2-one (5,4735 mg, 8.6 mmol) was added to a toluene solvent (86 mL) and thenstirred at room temperature for 15 min (so as to maximally preventagglomeration of Compound 5). Further, BSA (3.99 mL, 17.2 mmol) wasadded thereto and then the reaction was carried out at room temperaturefor 30 min. After 30 min, TBAF (tetrabutylammonium fluoride)-3H₂O (135.7mg, 0.43 mmol) was added thereto. After 20 to 30 min, when the reactionsolution became homogeneous, the reaction was terminated by the additionof AcOH (310 μL) diluted with MeOH (45 mL). The reaction solution wastreated using an evaporator to remove the solvent therefrom, after whichthe reaction was worked-up using a NaHCO₃ aqueous solution (60 mL) andethyl acetate (60 mL, 20 mL×3). The ethyl acetate layer was dried withanhydrous MgSO₄ and then filtered, followed by column chromatography(ethyl acetate:hexane=1:10), thus yielding a desired compound(3R,4S)-3-allyl-4-(4-(benzyloxy)phenyl)-1-(4-fluorophenyl)azetidin-2-one(6, 3033 mg, 91%) (FIGS. 7 to 9).

(3R,4S)-3-allyl-4-(4-(benzyloxy)phenyl)-1-(4-fluorophenyl)azetidin-2-one(6)

3033 mg, 91%, White solid; Rf=0.2 (ethyl acetate:hexane=1:2); ¹H NMR(400 MHz, CDCl₃) δ 7.43-7.33 (m, 5H), 7.26-7.23 (m, 4H), 6.98-6.91 (m,4H), 5.91-5.81 (m, ¹H), 5.18-5.11 (m, 2H), 5.05 (s, 2H), 4.62 (d, J=2.3Hz, ¹H), 3.20-3.16 (m, ¹H), 2.73-2.67 (m, ¹H), 2.59-2.51 (m, ¹H);¹³C{¹H} NMR (100 MHz, CDCl₃) δ 167.1, 159.2, 159.1 (J=243.0 Hz), 136.9,134.2 134.1 (J=2.5 Hz), 129.8, 128.8, 128.3, 127.6, 127.5, 118.6 (J=7.9Hz), 117.8, 115.9 (J=22.7 Hz), 115.6, 70.3, 60.5, 59.7, 32.9; ¹⁹F NMR(376 MHz, CDCl₃) δ −118.23; IR (KBr) 3034, 2916, 1748, 1639, 1509, 1382,1226, 1145 cm⁻¹; HRMS (EI) m/z: [M]⁺ Calcd for C₂₅H₂₂FNO₂ 387.1635;Found 387.1634.

Step (4): Synthesis of(3R,4S)-4-(4-(benzyloxy)phenyl)-1-(4-fluorophenyl)-3-((E)-3-(4-fluorophenyl)allyl)azetidin-2-one(Compound 8)

(3R,4S)-3-allyl-4-(4-(benzyloxy)phenyl)-1-(4-fluorophenyl)azetidin-2-one(6, 58.12 mg, 0.15 mmol), 1-fluoro-4-vinylbenzene (7, 179 μL, 1.5 mmol),a Grubbs 2^(nd) catalyst (6.37 mg, 0.0075 mmol) and CuI (2.86 mg, 0.015mmol) were added to an ether solvent (1.5 mL) and then reacted at 40° C.for 1 hr. The reaction solution was cooled to room temperature and thenfiltered through silica gel using ethyl acetate, followed by columnchromatography (ethyl acetate:hexane=1:10), thus yielding a desiredcompound(3R,4S)-4-(4-(benzyloxy)phenyl)-1-(4-fluorophenyl)-3-((E)-3-(4-fluorophenyl)allyl)azetidin-2-one(8, 50.56 mg, 70%) (FIGS. 10 to 12).

(3R,4S)-4-(4-(benzyloxy)phenyl)-1-(4-fluorophenyl)-3-((E)-3-(4-fluorophenyl)allyl)azetidin-2-one(8)

50.56 mg, 70%, White solid; Rf=0.2 (ethyl acetate:hexane=1:5); ¹H NMR(400 MHz, CDCl₃) δ 7.43-7.35 (m, 5H), 7.28-7.22 (m, 6H), 7.01-6.90 (m,6H), 7.01-6.93 (m, 4H), 6.44 (d, J=15.9 Hz, ¹H), 6.18-6.11 (m, ¹H), 5.04(s, 2H), 4.66 (d, J=2.3 Hz, ¹H), 3.28-3.24 (m, ¹H), 2.89-2.82 (m, ¹H),2.74-2.66 (m, ¹H); ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 166.9, 162.4 (J=246.7Hz), 159.2, 159.1 (J=243.3 Hz), 136.8, 134.1 (J=2.7 Hz), 133.2 (J=3.2Hz), 131.5, 129.8, 128.8, 128.2, 127.8 (J=7.9 Hz), 127.6, 127.4, 125.5(J=2.0 Hz), 118.6 (J=7.8 Hz), 115.9 (J=22.7 Hz), 115.7 (J=2.6 Hz),115.5, 70.3, 60.6, 60.0, 32.1; ¹⁹F NMR (376 MHz, CDCl₃) δ −114.64,−118.08; IR (KBr) 3034, 2917, 1748, 1610, 1509, 1385, 1227, 1175, 1157,1139 cm⁻¹; HRMS (EI) m/z: [M]⁺ Calcd for C₃₁H₂₅F₂NO₂ 481.1853; Found481.1855.

Step (5): Synthesis of(3R,4S)-4-(4-(benzyloxy)phenyl)-1-(4-fluorophenyl)-3-(3-(4-fluorophenyl)-3-oxopropyl)azetidin-2-one(Compound 9)

Pd(OAc)₂ (3.37 mg, 0.015 mmol), benzoquinone (81.07 mg, 0.75 mmol) and70% HClO₄ (0.15 M aqueous solution) (35 μL, 70 μL/mmol) were added to anacetonitrile solvent (1.25 mL), and then deoxygenated with stirring for30 min. Subsequently, H₂O (0.25 mL, 0.5 mL/mmol) was added thereto,followed by deoxygenation with vigorous stirring for 30 min.Subsequently,(3R,4S)-4-(4-(benzyloxy)phenyl)-1-(4-fluorophenyl)-3-((E)-3-(4-fluorophenyl)allyl)azetidin-2-one(8, 240.8 mg, 0.5 mmol) dissolved in acetonitrile (1.25 mL) was addeddropwise thereto. The reaction was carried out for 4 hr, after which 70%HClO₄ (0.15 M aqueous solution) (35 μL) was further added thereto, andthe reaction was then carried out for 12 hr. After completion of thereaction, the reaction was terminated with H₂O (30 mL) and extractionwas performed using ethyl acetate (15 mL, 5 mL×3). The ethyl acetatelayer was dried with anhydrous MgSO₄ and then filtered, followed bycolumn chromatography (ethyl acetate:hexane=1:5), thus yielding adesired compound(3R,4S)-4-(4-(benzyloxy)phenyl)-1-(4-fluorophenyl)-3-(3-(4-fluorophenyl)-3-oxopropyl)azetidin-2-one(9, 223.9 mg, 90%) (FIGS. 13 to 15).

(3R,4S)-4-(4-(benzyloxy)phenyl)-1-(4-fluorophenyl)-3-(3-(4-fluorophenyl)-3-oxopropyl)azetidin-2-one (9)

223.9 mg, 90%, White solid; Rf=0.2 (ethyl acetate:hexane=1:5); ¹H NMR(400 MHz, CDCl₃) δ 8.00-7.97 (m, 2H), 7.42-7.33 (m, 5H), 7.26-7.23 (m,4H), 7.12 (t, J=8.6 Hz, 2H), 6.97-6.91 (m, 4H), 5.04 (s, 2H), 4.67 (d,J=2.1 Hz, ¹H), 3.33-3.25 (m, ¹H), 3.19-3.11 (m, 2H), 2.44-2.35 (m, ¹H),2.31-2.22 (m, ¹H); ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 197.5, 167.4, 166.0(J=254.7 Hz), 159.2, 159.1 (J=243.4 Hz), 136.8, 134.0 (J=2.6 Hz), 133.2,(J=3.0 Hz), 130.9, 129.7, 128.8, 128.2, 127.5 (J=24.8 Hz), 118.6 (J=7.9Hz), 116.0 (J=7.3 Hz), 115.8 (J=6.5 Hz), 115.7, 70.3, 61.3, 60.0, 35.7,23.3; ¹⁹F NMR (376 MHz, CDCl₃) δ −104.93, −118.06; IR (KBr) 3064, 2922,2851, 1745, 1684, 1598, 1509, 1386, 1228, 1156 cm⁻¹; HRMS (EI) m/z: [M]⁺Calcd for C₃₁H₂₅F₂NO₃ 497.1803; Found 497.1806.

Step (6): Synthesis of(3R,4S)-4-(4-(benzyloxy)phenyl)-1-(4-fluorophenyl)-3-((S)-3-(4-fluorophenyl)-3-hydroxypropyl)azetidin-2-one (Compound 10)

A (R)-CBS catalyst [(R)-methyl-CBS (Corey-Bakshi-Shibata) catalyst](19.4 mg, 0.07 mmol) and(3R,4S)-4-(4-(benzyloxy)phenyl)-1-(4-fluorophenyl)-3-(3-(4-fluorophenyl)-3-oxopropyl)azetidin-2-one(9, 157.4 mg, 0.32 mmol) were dissolved in a THF (tetrahydrofuran)solvent (0.42 mL) and then stirred at −20° C. for 5 min. Subsequently, aborane dimethyl sulfide complex (Me₂S.BH₃) (2 M solution in THF) (192μL, 0.38 mmol) was added dropwise thereto at 0.5 mL/h, after which thereaction was carried out at −20° C. for 2 hr [chiral reduction]. Thereaction was terminated with MeOH (0.64 mL), and was then worked-upusing a 1 M HCl aqueous solution (20 mL) and 15 mL (5 mL×3) of ethylacetate. The extracted ethyl acetate layer was dried with anhydrousMgSO₄ and then filtered, followed by column chromatography(ether:hexane=1:2), thus yielding a desired compound(3R,4S)-4-(4-(benzyloxy)phenyl)-1-(4-fluorophenyl)-3-((S)-3-(4-fluorophenyl)-3-hydroxypropyl)azetidin-2-one (10, 147.1 mg, 92%) (FIGS. 16 to 18).

(3R,4S)-4-(4-(benzyloxy)phenyl)-1-(4-fluorophenyl)-3-((S)-3-(4-fluorophenyl)-3-hydroxypropyl)azetidin-2-one(10)

147.1 mg, 92%, White solid; Rf=0.2 (ether:hexane=1:2); ¹H NMR (400 MHz,CDCl₃) δ 7.42-7.33 (m, 5H), 7.30-7.21 (m, 6H), 7.02-6.90 (m, 6H), 5.0(s, 2H), 4.71-4.70 (m, ¹H), 4.57 (d, J=2.0 Hz, ¹H), 3.08-3.05 (m, ¹H),2.33 (s, ¹H), 1.99-1.86 (m, 4H); ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 167.8,162.3 (J=245.5 Hz), 159.2, 159.1 (J=243.5 Hz), 140.2 (J=3.1 Hz), 136.8,134.0 (J=2.4 Hz), 129.8, 128.8, 128.2, 127.6, 127.5 (J=8.1 Hz), 127.3,118.5 (J=7.9 Hz), 115.9 (J=22.7 Hz), 115.7, 115.5 (J=21.3 Hz), 73.2,70.3, 61.2, 60.4, 36.8, 25.1; ¹⁹F NMR (376 MHz, CDCl₃) δ −114.87,−118.10; IR (KBr) 3064, 3034, 2926, 2864, 1883, 1743, 1608, 1510, 1387,1223 cm⁻¹; HRMS (EI) m/z: [M]⁺ Calcd for C₃₁H₂₇F₂NO₃ 499.1959; Found499.1960.

Step (7): Synthesis of(3R,4S)-1-(4-fluorophenyl)-3-((S)-3-(4-fluorophenyl)-3-hydroxypropyl)-4-(4-hydroxyphenyl)azetidin-2-one (Compound 11)

(3R,4S)-4-(4-(benzyloxy)phenyl)-1-(4-fluorophenyl)-3-((S)-3-(4-fluorophenyl)-3-hydroxypropyl)azetidin-2-one (10, 258 mg, 0.5 mmol), 20% Pd(OH)₂/C (10.53 mg, 15 mol%) and cyclohexane (55.71 μL, 0.55 mmol) were added to a MeOH solvent(6.25 mL) under H₂ (1 atm) and then reacted at 70° C. for 3 hr[deprotection]. After completion of the reaction, the reaction productwas cooled to room temperature and then filtered through celite usingethyl acetate (25 mL). The filtered solution was concentrated and thenrecrystallized two times with MeOH and H₂O (1/3, 3 mL/9 mL). Theobtained solid was filtered using H₂O (20 mL), thereby yielding adesired compound(3R,4S)-1-(4-fluorophenyl)-3-((S)-3-(4-fluorophenyl)-3-hydroxypropyl)-4-(4-hydroxyphenyl)azetidin-2-one(11, 203 mg, 99%) (FIGS. 19 to 21).

(3R,4S)-1-(4-fluorophenyl)-3-((S)-3-(4-fluorophenyl)-3-hydroxypropyl)-4-(4-hydroxyphenyl)azetidin-2-one (11)

203 mg, 99%, White solid; Rf=0.2 (ethyl acetate:hexane=1:1); 99% ee;[α]²⁰ _(D) −28.05 (c 0.15, MeOH) [lit.¹ −28.1 (c 0.15, MeOH); ¹H NMR(400 MHz, CD₃OD) δ 7.34-7.27 (m, 4H), 7.21 (d, J=8.5 Hz, 2H), 7.06-6.96(m, 4H), 6.81 (d, J=8.5 Hz, 2H), 4.87 (s, 2H), 4.74 (d, J=2.0 Hz, ¹H),4.63-4.60 (m, ¹H), 3.10-3.07 (m, ¹H), 1.97-1.84 (m, 4H); ¹³C{¹H} NMR(100 MHz, CD₃OD) δ 169.9, 163.5 (J=243.6 Hz), 160.5 (J=242.0 Hz), 159.0,142.2 (J=3.0 Hz), 135.3 (J=2.7 Hz), 129.5, 128.8 (J=8.0 Hz), 128.6,119.9 (J=7.9 Hz), 117.0, 116.6 (J=22.9 Hz), 115.9 (J=21.6 Hz), 73.8,62.3, 61.2, 37.5, 26.1; ¹⁹F NMR (376 MHz, CD₃OD) δ −117.77, −120.15; IR(KBr) 2947, 2924, 1722, 1604, 1509, 1391, 1223 cm⁻¹; HRMS (EI) m/z: [M]⁺Calcd for C₂₄H₂₁F₂NO₃ 409.1489; Found 409.1488.

Although embodiments of the present invention have been described withreference to the accompanying drawings, those skilled in the art willappreciate that the present invention may be embodied in other specificforms without changing the technical spirit or essential featuresthereof. Thus, the embodiments described above should be understood tobe non-limiting and illustrative in every way.

The invention claimed is:
 1. A method of preparing ezetimibe, which is acompound of Chemical Formula 11, comprising: (1) obtaining a compound ofChemical Formula 3 below by reacting a compound of Chemical Formula 1below with a compound of Chemical Formula 2 below in the presence ofDIPEA (diisopropylethylamine) and DMAP (dimethylaminopyridine); (2)obtaining a compound of Chemical Formula 5 below by reacting thecompound of Chemical Formula 3 with a compound of Chemical Formula 4below in the presence of TiCl₄ and DIPEA; (3) obtaining a compound ofChemical Formula 6 below by reacting the compound of Chemical Formula 5in the presence of BSA (bis(trimethylsilyl) acetamide) and TBAF(tetrabutylammonium fluoride); (4) obtaining a compound of ChemicalFormula 8 below by reacting the compound of Chemical Formula 6 with acompound of Chemical Formula 7 below in the presence of a Grubbs 2ndcatalyst and CuI; (5) obtaining a compound of Chemical Formula 9 belowby reacting the compound of Chemical Formula 8 in the presence ofPd(OAc)₂, benzoquinone and HClO₄; (6) obtaining a compound of ChemicalFormula 10 below by reacting the compound of Chemical Formula 9 in thepresence of a (R)-CBS (Corey-Bakshi-Shibata) catalyst and a boranedimethyl sulfide complex; and (7) obtaining a compound of ChemicalFormula 11 below by reacting the compound of Chemical Formula 10 in thepresence of palladium hydroxide on carbon and cyclohexane:

wherein Bn is benzyl,

wherein Bn is benzyl,

wherein Bn is benzyl,

wherein Bn is benzyl,

wherein Bn is benzyl,

wherein Bn is benzyl,


2. The method of claim 1, wherein in step (1), the DIPEA is used in anamount of 1 to 3 equivalents based on an amount of Compound 1, and theDMAP is used in an amount of 1 to 10 mol % based on the amount ofCompound
 1. 3. The method of claim 1, wherein in step (2), the TiCl₄ isused in an amount of 0.5 to 2 equivalents based on an amount of Compound3, and the DIPEA is used in an amount of 1 to 3 equivalents based on theamount of Compound
 3. 4. The method of claim 1, wherein in step (3), theBSA is used in an amount of 1 to 3 equivalents based on an amount ofCompound 5, and TBAF is used in an amount of 1 to 10 mol % based on theamount of Compound
 5. 5. The method of claim 1, wherein in step (4), theGrubbs 2^(nd) catalyst is used in an amount of 1 to 10 mol % based on anamount of Compound 7, and the CuI is used in an amount of 1 to 50 mol %based on the amount of Compound
 7. 6. The method of claim 1, wherein instep (5), the benzoquinone is used in an amount of 0.5 to 5 equivalentsbased on an amount of Compound 8, and the Pd(OAc)₂ is used in an amountof 1 to 10 mol % based on the amount of Compound
 8. 7. The method ofclaim 1, wherein in step (6), the (R)-CBS catalyst is used in an amountof 1 to 50 mol % based on an amount of Compound 9, and the boranedimethyl sulfide complex is used in an amount of 0.5 to 5 equivalentsbased on the amount of Compound
 9. 8. The method of claim 1, wherein instep (7), the palladium hydroxide on carbon is used in an amount of 1 to30 mol % based on an amount of Compound 10, and the cyclohexane is usedin an amount of 0.5 to 5 equivalents based on the amount of Compound 10.9. A compound of Chemical Formula 5 below:

wherein Bn is benzyl.